The present invention relates to a medical method of treatment. More particularly, the present invention concerns the use of benzothiophene compounds, or a pharmaceutically acceptable salt thereof for the prevention of ulcer formation caused by nonsteroidal antiinflammatory drugs (NSAID) in a mammal. Particularly valuable is 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carbox amide.
Additionally, the present invention relates to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier for administering an effective amount of the aforementioned compounds in unit dosage form in the treatment method mentioned above.
NSAIDs are the most widely used drugs utilized for the treatment of rheumatic diseases (Agrawal N. M., et al., J. Rheumatol., 17:7-11, 1990). Although these agents can have significant beneficial effects by virtue of their antirheumatic and antiinflammatory effects, a significant side effect associated with this class of compounds is that they can cause gastrointestinal mucosal damage which may eventually lead to ulcers. The severity of this side effect can range from mild physical discomfort, to a discontinuation of the medication, or in the worst case of a bleeding ulcer, death of the patient.
Recently, it was reported in the literature (Wallace J. L., et al., Am. J. Physiol., 259:G462-467, 1990) that NSAID-induced gastric damage is a process not directly caused by NSAIDs but is indirectly mediated by neutrophils. Neutrophils are white blood cells (leukocytes) which normally reside and travel through blood vessels and provide the body with one of its defensive mechanisms against foreign infections. In the presence of local tissue stimulus such as that caused by a bacteria, adhesion receptors (P-selectin, E-selectin, intracellular cell adhesion molecule-1 (ICAM-1), etc.) are expressed locally on the walls of the blood vessels. These receptors interact with counter-receptors (L-selectin, macrophage receptor-1 (MAC-1), etc.) on the neutrophils allowing these cells to slow down via a rolling motion, stop and transmigrate into the tissue. This allows the offending bacteria to be attacked and killed by these migrating neutrophils. However, other stimulus such as that resulting from exposure to NSAIDs can also stimulate this adhesive event. In this case, normal tissue such as the gastric mucosa may be attacked inappropriately and damaged by the neutrophils.
Wallace, et al., have demonstrated that the NSAID-induced gastric damage can be prevented by either depleting the body of neutrophils or by blocking neutrophil adhesion using a monoclonal antibody directed against CD18, a component of the neutrophil adhesion molecule MAC-1 (Wallace J. L., et al., Gastroenterology, 100:878-883, 1991). These data highlight the pivotal role of neutrophil adhesion in the induction of NSAID related gastrointestinal damage.
U.S. Pat. No. 4,703,053, which is herein incorporated by reference, discloses certain benzothiophenes and benzofurans as antiallergy agents.
U.S. Pat. No. 4,910,317, which is herein incorporated by reference, discloses certain benzothiophenes and benzofurans as antiallergy agents, and in the treatment of cardiovascular disorders as well as antiinflammatory, antipsoriatic, antiulcer, and antimigraine agents.
U.S. Pat. No. 4,931,459, which is herein incorporated by reference, discloses certain benzothiophenes and benzofurans as agents for treating acute respiratory distress syndrome in humans.
Copending U.S. patent application Ser. No. 08/092,045 discloses the use of benzothiophenes and benzofurans as agents of therapeutic use in the treatment of inflammatory bowel disease.
It was recently discovered that 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carbox amide can inhibit neutrophil adhesion mediated by the adhesion molecule MAC-1 (Wright C. D., et al., Keystone symposium, P226, Feb. 20-26, 1994).
5-Methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxa mide inhibitory effect on the adhesion molecule MAC-1 is accompanied by its gastric cytoprotective effects against the damage caused by NSAIDs, such as indomethacin, and aspirin in rats (Low J. E., et al., Gastroenterology, 104:A137, 1993).
Thus, the object of the present invention is a medical method of treatment for the prevention of ulcer formation caused by NSAIDs with known benzothiophene compounds disclosed in U.S. Pat. No. 4,703,053.